Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study.

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Risk factors and treatment interventions associated with incomplete thrombus resolution and pulmonary hypertension after pulmonary embolism.

BACKGROUND: Residual pulmonary vascular occlusion (RPVO) affects one half of patients after a pulmonary embolism (PE). The relationship between the risk factors and therapeutic interventions for the development of RPVO and chronic thromboembolic pulmonary hypertension is unknown. METHODS: This retrospective review included PE patients within a 26-month period who had baseline and follow-up imaging studies (ie, computed tomography [CT], ventilation/perfusion scans, transthoracic echocardiography) available. We collected the incidence of RPVO, percentage of pulmonary artery occlusion (%PAO), baseline CT %PAO, most recent CT %PAO, and difference between the baseline and most recent %PAO on CT (Δ%PAO). RESULTS: A total of 354 patients had imaging reports available; 197 with CT and 315 with transthoracic echocardiography. The median follow-up time was 144 days (interquartile range [IQR], 102-186 days). RPVO was present in 38.9% of the 354 patients. The median Δ%PAO was -10.0% (IQR, -32% to -1.2%). Fewer patients with a provoked PE developed RPVO (P ≤ .01), and the initial troponin level was lower in patients who developed RPVO (P = .03). The initial thrombus was larger in the patients who received advanced intervention vs anticoagulation (baseline CT %PAO: median, 61.2%; [IQR, 27.5%-75.0%] vs median, 12.5% [IQR, 2.5%-40.0%]; P ≤ .0001). Catheter-directed thrombolysis (CDT; median Δ%PAO, -47.5%; IQR, -63.7% to -8.7%) and surgical pulmonary embolectomy (SPE; median Δ%PAO, -42.5; IQR, -68.1% to -18.7%) had the largest thrombus reduction compared with anticoagulation (P = .01). Of the 354 patients, 76 developed pulmonary hypertension; however, only 14 received pulmonary hypertension medications and 12 underwent pulmonary thromboendarterectomy. Cancer (odds ratio [OR], 1.7) and planned prolonged anticoagulation (>1 year; OR, 2.20) increased the risk of RPVO. In contrast, the risk was lower for men (OR, 0.61), patients with recent surgery (OR, 0.33), and patients treated with SPE (OR, 0.42). A larger Δ%PAO was found in men (coefficient, -8.94), patients with a lower body mass index (coefficient, -0.66), patients treated with CDT (coefficient, -18.12), and patients treated with SPE (coefficient, -21.69). A lower Δ%PAO was found in African-American patients (coefficient, 7.31). CONCLUSIONS: The use of CDT and SPE showed long-term benefit in thrombus reduction.

Computed Tomography Angiography-Based Pulmonary Artery Volumetry as a Diagnostic Tool for Pulmonary Hypertension.

OBJECTIVES: We evaluated use of three-dimensional pulmonary artery volumes derived from computed tomography pulmonary angiography (CTPA) in a group with pulmonary hypertension (PH) compared with healthy controls as a tool for the diagnosis of PH. METHODS: Retrospective analysis was performed of 40 CTPA scans obtained within 90 days of right heart catheterization demonstrating PH. The CTPA scans of 40 age- and sex-matched patients without cardiopulmonary disease were used as comparison. Diameters and volumes of the pulmonary arteries were compared. RESULTS: Adjusted total volume of the main, right, and left proximal pulmonary arteries (PAvol) demonstrated area under the curve of 0.918 (95% confidence interval, 0.860-0.975) for detection of PH, comparable to main pulmonary artery diameter measurement. Area under the curve values for PAvol were higher in subgroups divided by sex and PH severity. CONCLUSIONS: Volumetric analysis of the proximal pulmonary arteries using CTPA is a promising diagnostic tool for PH in a real-world cohort.

Phenotypes of Bronchopulmonary Dysplasia in Adults.

Bronchopulmonary dysplasia (BPD), first described by Northway in 1967, is a process of neonatal lung injury that is most strongly associated with prematurity. The "old" form of the disease associated with the oxidative damage and volutrauma from perinatal mechanical ventilation has been increasingly supplanted by a "new" form resulting from interrupted growth of the lung at earlier stages of fetal development. Given the significant improvement in the survival of children with BPD since the 1980s, many more of these patients are living into adulthood and are being seen in adult pulmonary practices. In this review, we present three brief vignettes of patients from our practice to introduce three of the major patterns of disease seen in adult survivors of BPD, namely, asthma-like disease, obstructive lung disease, and pulmonary hypertension. Additional factors shown to affect the lives of adult BPD survivors are also discussed. Finally, we discuss insights into the process of transitioning these complex patients from pediatric to adult pulmonary practices. As survivors of BPD enter adulthood and continue to require specialty pulmonary care, awareness of the disease's varied manifestations and responses to treatment will become increasingly important.

Right Heart Failure in Pulmonary Hypertension.

Right heart failure is a major cause of morbidity and mortality in pulmonary hypertension. Its pathophysiology is complex and involves both adaptive and maladaptive patterns of right ventricular change. In addition to the gold standard of right heart catheterization, noninvasive imaging such as echocardiography is useful in diagnosis and risk assessment. Management focuses on optimizing preload, reducing afterload, and supporting the function of the right ventricle with vasopressors and inotropes, if necessary. If required, mechanical support is increasingly used to facilitate recovery or as a bridge to transplant.

Novel dose-response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations.

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension. Apart from the inhaled formulation, there is neither a target dose nor a ceiling dose to guide clinicians using treprostinil; doses are individualized for each patient based upon tolerability and clinical improvement. Using combined data from the pivotal subcutaneous and oral treprostinil studies, we evaluated the effect of treprostinil dose on hospitalization and exercise capacity to better define the treprostinil dose-response relationship. Data from the pivotal subcutaneous and oral treprostinil studies were combined by converting oral doses to weight-based continuous doses (ng/kg/min) accounting for patient weight and bioavailability. Patients were divided into dose tertiles (lowest, middle, highest 33%) and retrospectively analyzed. Analysis 1 assessed the effect of dose on pulmonary arterial hypertension-related and all-cause hospitalizations. Analysis 2 evaluated the effects of dose on six-minute walk distance, Borg dyspnea score, and World Health Organization functional class. Results showed that, in Analysis 1, higher doses of treprostinil were associated with significantly longer times to first pulmonary arterial hypertension-related and all-cause hospitalization. In Analysis 2, there was a trend toward improvements in six-minute walk distance with higher doses. In patients with pulmonary arterial hypertension on systemic treprostinil therapy, higher doses were associated with significantly longer time to first pulmonary arterial hypertension-related and all-cause hospitalization. There was a trend toward improvements in six-minute walk distance. Collectively, these results underscore the importance of managing prostacyclin adverse events in order to achieve appropriate dose titration. Further studies are required to confirm these findings and to better characterize the dose-response relationship of treprostinil.

Pulmonary Hypertension in COPD: A Case Study and Review of the Literature.

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization.

Recent studies delineate a pathway involving familial Parkinson's disease (PD)-related proteins PINK1 and Parkin, in which PINK1-dependent mitochondrial accumulation of Parkin targets depolarized mitochondria towards degradation through mitophagy. The pathway has been primarily characterized in cells less dependent on mitochondria for energy production than neurons. Here we report that in neurons, unlike other cells, mitochondrial depolarization by carbonyl cyanide m-chlorophenyl hydrazone did not induce Parkin translocation to mitochondria or mitophagy. PINK1 overexpression increased basal Parkin accumulation on neuronal mitochondria, but did not sensitize them to depolarization-induced Parkin translocation. Our data suggest that bioenergetic differences between neurons and cultured cell lines contribute to these different responses. In HeLa cells utilizing usual glycolytic metabolism, mitochondrial depolarization robustly triggered Parkin-mitochondrial translocation, but this did not occur in HeLa cells forced into dependence on mitochondrial respiration. Declining ATP levels after mitochondrial depolarization correlated with the absence of induced Parkin-mitochondrial translocation in both HeLa cells and neurons. However, intervention allowing neurons to maintain ATP levels after mitochondrial depolarization only modestly increased Parkin recruitment to mitochondria, without evidence of increased mitophagy. These data suggest that changes in ATP levels are not the sole determinant of the different responses between neurons and other cell types, and imply that additional mechanisms regulate mitophagy in neurons. Since the Parkin-mitophagy pathway is heavily dependent on bioenergetic status, the unique metabolic properties of neurons likely influence the function of this pathway in the pathogenesis of PD.

Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model.

Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson's disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons.